Rotaviruses are consistently shown to be the single most important cause of severe diarrhea of infants and young children in both developed and developing countries. The consequences of rotavirus diarrhea are staggering as they account for up to 592,000 deaths annually in the under 5-year age group, predominantly in the developing countries (Parashar et al., Emerg. Infect. Dis., 2003, 9:565-572). It has recently been estimated that 1 in 200 children in developing countries will die from rotavirus diarrhea (Glass et al., Lancet, 2004, 363:1547-1550). In the United States, in the under 5-year age group, it was estimated that annually rotaviruses are responsible for 2,730,000 episodes of diarrheal illness, 410,000 visits to a physician, 160,000 emergency room visits, 50,000 hospitalizations, and 20 deaths (Tucker et al., JAMA, 1998, 279:1371-1376). Thus, the need for a rotavirus vaccine in both developed and developing countries has received national and international endorsement.
An oral, live, attenuated tetravalent rotavirus vaccine has been developed with the goal of inducing an immunologic response that mimicked natural rotavirus infection, especially with regard to induction of immunity at local intestinal sites (Kapikian et al., J. Infect. Dis., 1996, 174 Suppl 1:S65-72). This tetravalent vaccine was formulated to protect against the four epidemiologically important serotypes, numbered 1-4. Although the relative importance of homotypic vs. heterotypic immunity had not been established with certainty, it appeared from epidemiologic, clinical, animal, and laboratory observations that serotype-specific immunity was a major correlate of protection against rotavirus illness (Hoshino and Kapikian, J. Health Popul. Nutr., 2000, 18:5-14; Jiang et al., Clin. Infect. Dis., 2002, 34:1351-1361). The vaccine was comprised of representatives of each of 4 serotypes: rhesus rotavirus (RRV) which is a VP7 serotype 3 strain, (the Jennerian approach), and three human rotavirus-RRV reassortants, each possessing ten RRV genes and a single human rotavirus gene that encodes VP7 (a major outer capsid protein) that is responsible for serotype 1, 2, or 4 specificity (the modified Jennerian approach) (Kapikian et al., J. Infect. Dis., 1996, 174 Suppl 1:S65-72; Midthun et al., J. Virol. 1985, 53:949-954; Midthun et al., J. Clin. Microbiol. 1986, 24:822-826). Extensive clinical studies demonstrated the candidate vaccine's safety, immunogenicity and efficacy, especially against severe diarrhea (up to 91% efficacy) (Bernstein et al., JAMA, 1995, 273:1191-1196; Perez-Schael et al., N. Engl. J. Med., 1997, 337:1181-1187; Joensuu et al., Lancet 1997, 350:1205-1209; Santosham et al., J. Pediatr. 1997, 131:632-638, Rennels et al., United States Rotavirus Vaccine Efficacy Group. Pediatrics, 1996, 97:7-13). The vaccine protected against VP7 serotypes 1, 3, and 4 but could not be assessed for VP7 serotype 2 protection because of a paucity of such circulating strains in any of the major field trials (Bernstein et al., JAMA, 1995, 273:1191-1196; Perez-Schael et al., N. Engl. J. Med., 1997, 337:1181-1187; Joensuu et al., Lancet 1997, 350:1205-1209; Santosham et al., J. Pediatr. 1997, 131:632-638; Rennels et al., United States Rotavirus Vaccine Efficacy Group. Pediatrics, 1996, 97:7-13). In addition, in comparative trials of vaccine efficacy, the tetravalent vaccine induced a higher degree of protection, overall, than a monovalent vaccine when the infecting serotype was heterotypic to that of the monovalent vaccine (Bernstein et al., JAMA, 1995, 273:1191-1196; Santosham et al., J. Pediatr. 1997, 131:632-638; Rennels et al., United States Rotavirus Vaccine Efficacy Group. Pediatrics, 1996, 97:7-13).
The U.S. Advisory Committee on Immunization Practices (ACIP) recommended routine administration of the tetravalent vaccine to infants at 2, 4, and 6 months of age (Recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 1999, 48:all (1-20)). Subsequently, in August 1998, the U.S. Food and Drug Administration (FDA) granted a Biologics License for the vaccine (RotaShield™) to Wyeth Laboratories (Recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 1999, 48:all(1-20)). However, in July 1999, after over one million doses of the vaccine had been given, the U.S. Centers for Disease Control and Prevention (CDC) recommended suspending its further use pending additional studies because of a link with intussusception, especially in the first two weeks after the first dose. Approximately 3 months later, after reviewing additional data, the ACIP withdrew its recommendation for use of the vaccine.
This decision has continued to generate intense discussion and controversy in the scientific community because of continuing disagreements about the actual magnitude of the risk of the vaccine with respect to intussusception and because of related risk-benefit issues. These debates are fueled by the realization that up to approximately 1600 infants and young children worldwide die daily from a disease that might be prevented if RotaShield™ were available for these settings and by the reality that developing countries will not use a vaccine that has been withdrawn for safety reasons in the U.S. Data from CDC indicated initially that the excess risk of intussusception occurring after RotaShield™ was given, was as great as 1.8 based on a case-control study (i.e., up to an 80% excess in the number of cases over background, which corresponds to 1 excess case per 2500 vaccines). From these estimates CDC projected that in a full national vaccination program in the U.S. there would be up to 1600 excess cases over the background estimate of 2000 cases. However, the relative risk figures have undergone considerable downward revisions including estimates of: (i) 1:10,000 excess cases as a consensus figure; (ii) 1:32,000-1:302,000 excess cases in 45-210 day old infants in population-based hospital discharge studies; and (iii) no increase in the number of hospitalizations from intussusception in the under one year age group because of a likely compensatory decrease.
More recently, age at vaccination was shown to be an important factor in the development of intussusception as vaccines who were 90 days of age or older at first dose experienced a disproportionately greater number of cases (81%) than infants who were <90 days of age, with no cases in infants vaccinated at <60 days of age during the two weeks after the first dose in CDC's case-control study. According to analysis of the CDC National Immunization Survey in the 19 states of the case-control study, the ≧90 day old age group had received 38% of all first doses and in addition, the <60 day old group received 16% (approximately 70,000 infants) of all first doses. Thus “catch-up” vaccination of older infants (first dose given to infants beyond the ideally recommended age of two months) was responsible for a substantial portion of the intussusception cases observed in this study.
Concurrent with the development of human rotavirus-RRV reassortants described above, single gene substitution human rotavirus-bovine rotavirus (UK) reassortants have been developed that comprise 10 genes from the bovine (UK) strain and a gene that encodes VP7 the major outer capsid protein for each of the human rotavirus serotype 1, 2, 3, or 4 strains (Midthun et al, J. Virol. 53:949-954 (1985); Midthun et al., J. Clin. Microbiol. 24:822-826 (1986)). These reassortant constructs were considered our second-generation vaccine because studies with bovine strain NCDV had demonstrated that NCDV induced febrile reactions significantly less often than did the rhesus rotavirus strain vaccine (Vesikari et al., J. Infect. Dis. 153:832-839 (1986)). For example in a direct comparison of febrile responses (≧38° C. or 100.4° F. rectally) following vaccination with monovalent RRV or NCDV, RRV induced a febrile response significantly more often than NCDV (64% vs 17%) (Vesikari et al., supra). This was considered to be an advantage for the bovine strain. In addition, as self-limited febrile episodes were also observed with the tetravalent formulation of the rhesus rotavirus-based vaccine (Bernstein et al., JAMA 1995, 273:1191-1196; Perez-Schael et al., N. Engl. J. Med. 1997, 337:1181-1187; Joensuu et al., Lancet 1997, 350:1205-1209; Santosham et al., J. Pediatr. 1997, 131:632-638; Rennels et al., Pediatrics 1996, 97:7-13), we continued to pursue the bovine rotavirus (UK)-based tetravalent vaccine actively as the second-generation vaccine.
In order to achieve the goal of introducing the bovine UK-based reassortant vaccine as our second-generation vaccine, we have carried out phase 1, 2 and 3 clinical studies, and as described later, new candidate strains were also generated representing emerging serotypes that could be used in countries where such rotavirus strains were prevalent. These studies have been carried out in stepwise fashion as summarized below:                (1) Studies of the safety and immunogenicity of each of the 4 monovalent human-bovine rotavirus (UK) reassortant strains with VP7-specificity for serotypes 1, 2, 3, or 4, sequentially in adults (one dose), children (one dose) and infants (one or two doses) (Clements-Mann et al., Vaccine 1999, 17:2715-2725). Each component demonstrated satisfactory attenuation, safety, infectivity and immunogenicity in the target population of infants 1.5-5.9 months of age;        (2) Studies of the safety and immunogenicity of the 4 serotypes combined into a tetravalent formulation of the human-bovine (UK) reassortant vaccine with VP7 specificity for serotypes 1, 2, 3, and 4, in stepwise fashion in adults (one dose), children (one dose), and infants (three doses) (Clements-Mann et al., Vaccine 2001, 19:4676-4684). The tetravalent formulation demonstrated satisfactory attenuation, safety, infectivity and immunogenicity in the target population that received the first dose at 1.5-2.5 months of age. In addition, when given concurrently, the tetravalent formulation did not inhibit antibody responses to DTP, HIb, hepatitis B or oral polio vaccine;        (3) The tetravalent human-bovine (UK) reassortant vaccine was evaluated for safety, immunogenicity, and efficacy in a field trial in Finland employing two sequential doses, one at approximately 2 months and the other at about 4 months of age in approximately 170 vaccines and approximately 85 controls. It was shown to be safe, and in contrast to the tetravalent rhesus rotavirus-based vaccine, which was also being evaluated in Finland concurrently in a study of approximately the same size, it did not induce febrile episodes at a frequency significantly greater than that of the placebo group. The tetravalent human-bovine (UK) vaccine induced over 80% protection against severe rotavirus diarrhea, an efficacy level comparable to that observed with the tetravalent rhesus rotavirus-based vaccine.        